US4933184A - Menthol enhancement of transdermal drug delivery - Google Patents
Menthol enhancement of transdermal drug delivery Download PDFInfo
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- US4933184A US4933184A US07/034,803 US3480387A US4933184A US 4933184 A US4933184 A US 4933184A US 3480387 A US3480387 A US 3480387A US 4933184 A US4933184 A US 4933184A
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- drug
- menthol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
Definitions
- transdermal drug delivery systems have increased resulting in a number of commercially available products especially for the administration of nitroglycerine. These latter systems apparently provide the advantages inherent in sustained delivery dosage forms and avoid the problems of a drug's rapid metabolism upon oral administration. At the same time less drug, although equally efficacious therapeutically to a greater amount orally administered, is ingested or absorbed by the patient. Nevertheless, the feasibility, the success and potential of such transdermal systems have heretofore been limited to drugs that are efficacious at lower dose levels and/or have relatively limited water solubility. The explanation for such limitations arise from the daunting barrier provided by the external layer(s) of animal skin and membrane tissues and the limited body areas which are usefully available for application of such transdermal dosage forms.
- Agents reported to act as penetration enhancers for transdermal drug delivery include dimethylsulfoxide, disclosed in U.S. Pat. No. 3,551,554; combinations of sucrose fatty acid esters with a sulfoxide or phosphoric oxide, disclosed in U.S. Pat. Nos. 3,896,238; 3,952,099 and 4,046,886; and the 1-substituted azacycloalkan-2-ones which are the subject of U.S. Pat. Nos. 3,989,816; 4,316,893 and 4,405,616.
- the present invention relates to compositions useful for the transdermal delivery of physiologically active agents to mammals. More particularly, this invention relates to compositions and methods which enhance the percutaneous transfer of topically applied, systemically active drugs and particularly such drugs which have aqueous solubility or which can be made water soluble by the use of derivatives, or in composition, through selection of appropriate pH, buffers, solvents and excipients.
- the composition of this invention comprises at least one systemically active, water soluble or solubilizable drug, a percutaneous transfer enhancing amount of menthol and a pharamceutically acceptable vehicle in which the menthol is soluble.
- the invention relates to a method for enhancing the transfer of physiologically active agents into and through mammalian skin and membranes.
- the method comprises topically applying or administering to substantially the same section of the mammalian skin or membrane an effective amount of a systemically active, water soluble or solubilizable drug, a percutaneous transfer enhancing amount of menthol and a pharmaceutically acceptable vehicle.
- Still a further embodiment of this invention resides in a unit dosage form for transdermal delivery of physiologically active agents to mammals.
- the dosage form comprises an effective amount of a systemically active, water soluble or solubilizable drug comprised within at least one drug reservoir means; a percutaneous transfer enhancing amount of menthol comprised within menthol delivery means; menthol solubilizing means and securing means for attaching the dosage form to a mammal.
- Menthol is a secondary alcohol obtained naturally from peppermint or other mint oils or prepared synthetically. Menthol has many uses as an ingredient in various medicinal preparations due to its analgesic, local anesthetic and counter irritant properties. It has now been found that menthol acts to enhance the percutaneous transfer of systemically active drugs in mammal.
- physiologically active agent(s) or “drug(s)” do not include either menthol or indomethacin in their definition.
- this invention provides a topical composition for the transdermal and sustained delivery of physiologically active agents to mammals, said composition comprising an effective amount of a systemically active, water soluble or solubilizable drug, a percutaneous transfer enhancing amount of menthol and a pharmaceutically acceptable vehicle comprising at least one pharmaceutically acceptable solvent or solubilizer for said menthol.
- the effective amount of drug will mean that amount of drug needed to produce a therapeutic dose following its transdermal administration. That amount will vary, depending, among other factors, on the physiological effect desired, the frequency of administration, drug and intradermal metabolism, drug half-life and the amount of menthol and perhaps other percutaneous transfer enhancers employed in the composition.
- a percutaneous transfer enhancing amount of menthol is comprised in the composition. This amount for most drugs, generally ranges from about 4 to about 16 percent by weight of the composition.
- composition of the invention will further include a pharmaceutically acceptable vehicle containing at least one pharmaceutically acceptable solvent or solubilizer for said menthol.
- vehicle in preferred compositions will also contain at least one pharmaceutically acceptable solvent which is a solvent or solubilizer for the drug.
- the respective solvents or solubilizers for the drug and menthol of this invention may be the same or different. In either case it is preferable that the solvents or solubilizers for each the drug and menthol, in the amounts employed, are at least partially soluble or miscible with each other. Most preferably, the solvents or solubilizers for each the drug and the menthol will, in the amounts employed, be wholly soluble or miscible with each other.
- the pharmaceutically acceptable vehicle may also contain other pharmaceutically acceptable excipients useful for formulating topical pharmaceutical compositions including buffers, neutralizing agents, pH modifiers, viscosity building or controlling agents, gel forming agents, emulsifiers, surfactants, polymers and the like.
- the method and composition of this invention generally provide at least two fold enhancement of the delivery of water solubilizable drugs and five fold enhancement of the delivery of water soluble drugs, at least in in vitro models, and, preferably three fold and ten fold enhancement respectively.
- systemically active drugs or their salts examples include:
- Coronary vasodilators such as isosorbide dinitrate
- Corticoids such as hydrocortisone
- Analgesics and Antiinflammatory agents such as ibuprofen, etodolac, pemodolac and ketoprofen but not indomethacin;
- Antidiabetics such as chlorpropamide
- Aldose reductase inhibitors such as tolrestat
- Bronchodilators such as albuterol
- Antihistamines such as chlorpheniramine
- Decongestants such as phenylpropanolamine
- Estrogens and progestogens including those of natural or synthetic orgin such as estradiol, norgesterel, conjugated estrogens such as PREMARIN, and medroxyprogesterone;
- Beta blockers such as propanolol, cetamolol and atenolol
- Cardiotonics such as pelrinone and digoxin
- Peptide hormones such as insulin and somatostatin
- Agonists such as nicotine
- a preferred group of drugs are those selected from the group consisting of etodolac, chlorpheniramine, propanolol, estrogens, progestogens and their pharmeceutically acceptable salts.
- Another preferred group of drugs are those selected from the group consisting of cetamolol, acifran, phenylpropanolamine, ibuprofen, nicotine, diazepam, digoxin, insulin, somatostatin, isosorbide dinitrate, vinpocetine, pelrinone, hydrocortisone and their pharmaceutically acceptable salts.
- the method or composition of the invention utilize the drug and its pharmaceutically acceptable salt together.
- composition of this invention for application to mammalian skin or membrane may take various forms including creams, lotions, gels, ointments, suppositories, sprays, aerosols and the like.
- the invention includes a method for treating mammals in need of treatment with systemically active agents by the transdermal administration of said agents sequentially or in combination with a percutaneous transfer enhancing amount of menthol.
- the method is effected by topically administering to substantially the same section of mammalian skin or membrane an effective amount of a systemically active, water soluble or solubilizable drug, a percutaneous transfer enhancing amount of menthol and a pharmaceutically acceptable vehicle.
- the method of the invention may also be employed as referred to hereinabove in the Summary of the Invention as a method for enhancing the transfer of physiologically active agents through mammalian skin and membranes.
- the method may be realized through administration of the composition of the invention, a unit transdermal dosage form comprising the composition of the invention, or through sequential administration of the percutaneous transfer agent and drug of this invention via direct application to said mammal or via the unit transdermal dosage form of this invention comprising the same or different means for delivery of each of said percutaneous transfer agent and said drug.
- the unit dosage form of this invention as hereinbefore described comprises an effective amount of a systemically active water soluble or solubilizable drug comprised within at least one drug reservoir means.
- Said drug reservoir means may take various forms such as pads or sponges impregnated with drug, a polymeric matrix containing the drug or composition of the drug, a gel formulation (or other formulation having some structural integrity) of the drug, a composition or solution of the drug within a walled container permeable to the drug and available to the skin or membrane of the mammal, a multiplicity of distinct microreservoir compartments containing the drug or drug composition within or homogenously throughout each microreservoir, layers of reservoirs and multiple variants of any of these enumerated and other drug reservoir presentations.
- the unit dosage form as with the other embodiments of this invention, further comprises a percutaneous transfer enhancing amount of menthol.
- the menthol will be comprised within menthol delivery means which means can be selected from any of the described drug reservoir means, distinct menthol reservoir means and integral menthol reservoir means.
- Integral menthol reservoir means is defined to include the provision of the menthol together with the securing means, as for example in an adhesive layer.
- Menthol solubilizing means and securing means for attaching or maintaining contact of the dosage form to a mammal are also comprised by the unit dosage form of the invention.
- the menthol solubilizing means comprise a pharmaceutically acceptable vehicle in which the menthol is soluble or solubilizable and which further is also either a solvent for the drug or is miscible with the drug or drug composition.
- the menthol solubilizing means may be formulated with any of the menthol, the drug and/or in a distinct reservoir or depot within the unit dosage of the invention, so long as the menthol is soluble or made soluble therein and the drug or drug composition is soluble or miscible therewith prior to transfer through the skin or membrane of the mammal.
- the securing means will be selected from adhesives, belts such as those with "velcro" fittings, elastic bands or such other devices which are capable of securely attaching the unit dosage to the mammalian subject.
- in-vitro percutaneous transfer tests with nude mouse skins were performed as follows; A piece of freshly excised nude mouse skin was mounted across a 6 cm 2 opening of a diffusion cell. The test formulation was first impregnated into 1-inch diameter circles of a thin non-woven rayon fabric usually in amounts representing about 20 mg or more per cm 2 of skin. The impregnated fabric was applied to the outside or epidermal side of the skin while the inside or tissue side of the skin was exposed to an aerated and stirred volume of Ringer's injection fluid maintained at about 37° C. Samples were taken at intervals from the stirred solution and assayed for drug content. The calculated total amount of percutaneously transferred drug is expressed as mg drug per cm 2 of exposed skin.
- Formulation B was prepared according to methods described in U.S. Pat. Nos. 3,952,099 and 4,046,886. Two circles of non-woven fabric were impregnated with each formulation (designated A1, A2 and B1, B2 respectively) and tested for percutaneous drug transfer across nude mouse skin.
- the menthol formulation caused much higher transfer than the reference formulation. The difference was larger than the skin-to-skin variation seen in the duplicate runs.
- Formulations containing conjugated estrogens were prepared.
- a purified and dried concentrate of Conjugated Equine Estrogens was used, which contained per gram, 324 mg of conjugated estrogens when assayed according to the methods specified in the XX. edition of the U.S. Pharmacopeia.
- the major components of this mixture of natural estrogens are sodium estrone sulfate (about 54%), sodium equilin sulfate (about 29%), and sodium dihydroequilin sulfate (about 13%).
- the formulation ingredients, as given below in percentages by weight, were combined, then warmed and stirred to give hazy amber solutions.
- the formulation without menthol did not allow the passage of detectable amounts of estrogen across the skin.
- the two menthol containing formulations caused the transfer of large amounts of estrogens. All three of the major constituents penetrated the skin, in proportions essentially equal to the original mixture composition.
- Formulations containing etodolac, 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, a non-steroidal antiinflammatory, analgesic agent were prepared with and without 5% menthol in a glycerol/propylene glycol vehicle.
- the agent, sparingly soluble in water, but solubilized by this vehicle demonstrated about a three fold increase in percutaneous transfer in the presence of menthol.
- the aqueous solubility of the etodolac were increased via the employment of buffers and/or alkalizing agents the enhancing effect of menthol was even more pronounced in the nude mouse skin studies.
- Formulation containing 17- ⁇ -estradiol (a non-water soluble estrogen) in lipophilic vehicles with and without menthol demonstrated no significant differences in percutaneous transfer.
- formulations containing menthol demonstrated significantly higher flux rates in the nude mouse skin studies.
- the indicated test formulation was impregnated into non woven rayon patches (reservoirs).
- the patches (about 0.79 cm 2 ) were then applied to the strateum corneum side of the indicated test skin and maintained thereat by application of an occlusive backing.
- the test skin had been previously mounted across the opening of diffusion cell which contained phosphate buffer (pH 7.4) maintained at 32° C. as the receiving fluid, stirred past the skin. Sample volumes removed for assay were replaced by an equal volume of fresh phosphate buffer.
- the units employed in the formulation are expressed as percent w/w (weight/weight). Other units of measurement not specifically expressed are:
- AD Amount diffused (mcg.)
- Formulation A with menthol was over 4 times as effective as Formulation B with methyl salicylate.
- Formulations containing vinpocetine comparing the relative enhancement of menthol versus peppermint oil were prepared:
- Formulation B In triplicate or duplicate runs (at different times) through mouse skin, Formulation B with peppermint oil, surprisingly, provided no enhancement over Formulation A.
- Formulations C and D provided on the order of 11 and 18 fold enhancement respectively over Formulation A.
- Formulations containing propanolol hydrochloride and terpin hydrate, a compound with a structure similar to menthol were loaded onto non-woven patches and evaluated on hairless mouse skin. In duplicate runs conducted over 23 hours, the terpin hydrate containing formulation did not show any enhancing activity.
- the formulation tested was:
Abstract
Description
______________________________________ percent by weight A B ______________________________________ Propanolol hydrochloride 55.6 29.6 Glycerol 26.6 47.8 Propylene glycol -- 8.1 Menthol 17.8 -- n-Decylmethylsulfoxide -- 3.8 sucrose stearate -- 10.7 ______________________________________
______________________________________ Al A2 B1 B2 ______________________________________ Amount of drug present in 10.95 8.83 5.17 5.83 formulation applied to epider- mal surface (mg/cm.sup.2) Amount of drug passing across skin (mg/cm.sup.2) after 2 hours 0.01 0.003 0.004 0.005 4 hours 1.05 0.20 0.02 0.03 6 hours 1.49 0.91 0.06 0.06 9 hours 8.27 2.83 0.18 0.12 12 hours 8.83 3.48 0.37 0.18 22 hours 9.20 4.93 1.31 0.50 ______________________________________
______________________________________ Formulation C D E ______________________________________ Dried concentrate of Conjugated Estrogens 4.1 4.1 5.0 Propylene glycol 64.3 64.1 64.9 Isopropanol 16.1 12.0 8.1 Water 15.5 15.8 13.9 Menthol 0 4.0 8.1 ______________________________________
______________________________________ C D E ______________________________________ Sodium estrone sulfate (μg/cm.sup.2) passing across skin after 2 hours 0 0 2 4 hours 0 1 32 6 hours 0 7 101 13 hours 0 46 164 22 hours 0 99 223 Sodium equilin sulfate (μg/cm.sup.2) passing across skin after 2 hours 0 0 0.6 4 hours 0 0.2 13 6 hours 0 3 44 13 hours 0 19 84 22 hours 0 44 103 Sodium dihydroequilin sulfate (μg/cm.sup.2) passing across skin after 2 hours 0 0 0.3 4 hours 0 0.2 7 6 hours 0 2 25 13 hours 0 11 45 22 hours 0 28 62 ______________________________________
______________________________________ weight percent A B ______________________________________ Propanolol hydrochloride 18.02 17.98 Glycerin 54.10 63.88 Isopropanol 17.84 18.14 Menthol 10.04 -- ______________________________________
______________________________________ Mean in ng/ml Time (Hours) A B ______________________________________ 1 0.8 5.5 2 165.5 6.0 3 140.0 9.5 4 115.5 9.0 6 457.0 4.5 8 491.0 0.8 12 922.0 4.5 16 1317.0 11.5 24 628.0 6.5 32 73.5 1.8 ______________________________________
______________________________________ Formulations A B C D E F ______________________________________ Menthol -- -- 5.14 9.88 9.97 15.11 1-Methyl-2-pyrrolidone 23.85 23.78 22.48 21.75 21.20 20.14 Albuterol 5.07 5.01 5.04 4.86 4.90 4.96 Diethylene Glycol 71.08 71.21 67.35 63.51 63.93 59.79 Monoethylether ______________________________________
______________________________________ Results - Albuterol Total Flux Formulation [m] AD % D Flux Ratio ______________________________________ A-1 0 393.32 35.11 31.67 A-2 0 267.30 27.27 23.91 Avg. 330.31 31.19 27.79 B-1 0 408.82 43.18 40.56 B-2 0 285.32 29.97 26.65 Avg. 338.69 33.88 30.70 (A + B) C-1 5.14 821.75 70.28 74.57 C-2 5.14 992.89 89.96 103.08 Avg. 907.32 80.12 88.82 2.89 D-1 9.88 991.88 92.35 150.69 D-2 9.88 950.73 89.33 112.35 Avg. 971.30 90.84 131.52 4.28 E-1 9.97 1036.07 99.27 128.09 E-2 9.97 1000.62 95.87 107.18 Avg. 1018.34 97.57 117.64 3.83 F-1 15.11 969.95 90.12 126.49 F-2 15.11 1004.49 93.76 118.12 Avg. 987.22 91.94 122.30 3.98 ______________________________________
______________________________________ Formulations A B C ______________________________________ Menthol -- 5.00 9.75 Water 24.30 23.09 22.67 Albuterol Sulfate 5.01 4.91 4.91 Diethylene Glycol Monoethylether 70.69 67.00 62.67 ______________________________________
______________________________________ Results - Albuterol Sulfate Total Flux Formulation [m] AD % D Flux Ratio ______________________________________ A-1 0 141.40 12.17 11.69 A-2 0 99.91 8.86 8.19 A-3 0 62.24 5.78 5.46 Avg. 101.18 8.94 8.45 B-1 5.00 792.90 74.45 55.45 B-2 5.00 1039.98 92.93 85.34 Avg. 916.44 83.69 70.44 8.34 C-1 9.75 931.12 86.61 64.05 C-2 9.75 780.92 75.74 57.43 Avg. 856.02 81.18 60.74 7.19 ______________________________________
______________________________________ Formulations A B ______________________________________ Menthol -- 9.64 1-methyl-2-pyrrolidone 80.12 70.81 Hydrocortisone (radiolabeled) 19.88 19.55 ______________________________________
______________________________________ Results - Hydrocortisone Total Flux Formulation [m] AD % D Flux Ratio ______________________________________ A-1 0 228.79 7.28 15.1 A-2 0 169.45 5.57 9.8 Avg. 199.12 6.42 12.4 B-1 9.64 319.60 11.12 36.50 B-2 9.64 464.28 14.66 35.21 Avg. 391.94 12.89 35.86 2.89 ______________________________________
______________________________________ Formulations A B C D ______________________________________ Menthol 0 4.91 9.96 10.16 17-β-estradiol 1.06 1.22 0.80 0.81 Propylene Glycol 98.94 93.87 89.24 89.03 ______________________________________
______________________________________ Results - 17-β-estradiol Total Flux Formulation [m] AD % D Flux Ratio ______________________________________ A 0 1.6 1.4 0.021 B-1 4.91 11.4 4.8 0.56 B-2 4.91 9.5 3.8 0.69 Avg. 10.45 4.3 0.62 29.52 C-1 9.96 9.31 6.44 0.209 C-2 9.96 11.2 11.6 0.403 C-3 9.96 14.5 14.0 0.422 Avg. 11.00 10.68 0.345 16.43 D-1 10.16 5.22 3.75 0.178 D-2 10.16 11.62 8.86 0.306 Avg. 8.42 6.30 0.24 11.43 ______________________________________
______________________________________ Formulations A B C D E ______________________________________ Menthol -- 1.15 4.99 10.06 15.00 Chlorpropamide 5.16 5.08 4.99 4.87 5.05 N-methyl-2-pyrrolidone 94.84 93.77 90.02 85.57 79.94 ______________________________________
______________________________________ Results - Chlorpropamide Total Flux Formulation [m] AD % D Flux Ratio ______________________________________ A-1 0 117.67 11.42 7.32 A-2 0 127.49 12.38 9.10 Avg. 122.58 11.90 8.21 B-1 1.15 169.50 17.47 10.97 B-2 1.15 316.97 31.08 18.40 Avg. 243.24 24.28 14.68 1.79 C-1 4.99 448.63 45.78 23.94 C-2 4.99 781.56 80.57 37.09 Avg. 615.10 63.18 30.52 3.72 D-1 10.06 877.96 91.45 38.52 D-2 10.06 597.10 60.93 36.78 Avg. 757.53 76.19 37.65 4.59 E-1 15.00 906.34 87.99 44.15 E-2 15.00 1053.18 96.62 39.31 Avg. 979.76 92.30 41.73 5.08 ______________________________________
______________________________________ Formulations A B ______________________________________ Menthol -- 9.19 Propranolol HCl 14.14 14.71 Glycerin 64.64 56.89 Isopropanol 21.23 19.22 ______________________________________
______________________________________ Results - Propranolol HCl Total Flux Formulation [m] AD % D Flux Ratio ______________________________________ A-1 0 10.00 0.07 0.5 A-2 0 20.00 0.21 0.5 Avg. 15.00 0.14 B-1 9.19 440.00 3.76 3.00 B-2 9.19 1890.00 16.50 20.00 Avg. 1165.00 10.13 11.50 ______________________________________
______________________________________ Formulations A B ______________________________________ Menthol -- 10.18 Acebutolol HCl 29.85 29.28 4:1 Propylene Glycol:Water 70.15 60.54 ______________________________________
______________________________________ Results - Acebutolol HCl Total Flux Formulation [m] AD % D Flux Ratio ______________________________________ A-1 0 1050.86 2.29 12.00 A-2 0 523.39 1.10 6.00 Avg. 787.12 1.70 9.00 B-1 10.18 34554.72 72.09 480.00 B-2 10.18 33458.21 79.57 470.00 Avg. 34006.46 75.83 475.00 52.78 ______________________________________
______________________________________ Formulations A B ______________________________________ Menthol -- 11.39 Tolrestat 14.77 15.29 Propylene Glycol 85.23 73.32 ______________________________________
______________________________________ Results - Tolrestat Total Flux Formulation [m] AD % D Flux Ratio ______________________________________ A-1 0 420.00 1.63 6.00 A-2 0 610.00 2.34 6.00 Avg. 515.00 1.98 6.00 B-1 11.39 13770.00 51.31 220.00 B-2 11.39 7620.00 28.33 100.00 Avg. 10695.00 39.82 160.00 26.67 ______________________________________
______________________________________ percent by weight A B ______________________________________ Premarin ® 8.4 8.4 Propylene glycol 60 60 Ethanol 16 16 Water 8 8 Menthol 8 -- Methyl Salicylate -- 8 ______________________________________
______________________________________ percent by weight A B C D ______________________________________ Vinpocetine 5 5 5 5 N-methyl-2-pyrrolidone 95 85 90 85 Peppermint Oil -- 10 -- -- Menthol -- -- 5 10 pH.sub.3 ______________________________________
______________________________________ percent by weight ______________________________________ Terpin hydrate 13 Propranolol hydrochloride 43.5 Propylene glycol 16 Glycerol 27 ______________________________________
Claims (16)
Priority Applications (1)
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US07/034,803 US4933184A (en) | 1983-12-22 | 1987-04-03 | Menthol enhancement of transdermal drug delivery |
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US56465483A | 1983-12-22 | 1983-12-22 | |
US07/034,803 US4933184A (en) | 1983-12-22 | 1987-04-03 | Menthol enhancement of transdermal drug delivery |
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